Low exercise capacity or cardiorespiratory fitness is comparable to elevated systolic blood pressure, obesity, diabetes, and smoking as a risk factor and predictor of future disease. However, there is a high degree of individual variation in cardiorespiratory fitness before and after exercise training, including individuals that may not respond at all to training. Non-responding individuals might not benefit from increased physical activity and may be at higher risk for diseases related to low fitness, such as cardiovascular disease, metabolic syndrome, and breast and colon cancer. Although many of the phenotypic traits associated with exercise training are well known (i.e., increased oxidative metabolism, improved endothelial function), the genetic factors determining the magnitude of the response to exercise are poorly understood. Therefore, the objective of this proposal is to use quantitative trait loci (QTL) mapping to identify novel candidate genes that influence the variation in exercise training responses. By this approach, the PI has identified potential QTL for exercise-training responses on chromosomes 2, 12, and 14 (LOD 3.49 - 6.25) using F2 mice generated from an intercross of C57BI/6J (low response to training) and FVB/NJ (high response to training) inbred strains. These exciting preliminary data suggest that variation in the responses to exercise training (trainability) is affected by specific chromosomal regions and likely specific genes. Therefore, based on these preliminary data the PI proposes to test the hypothesis that a small number of QTL are critical for determining the adaptations to exercise training. In Aim 1 the PI will identify QTL that affect variation in exercise training adaptations based on changes in exercise performance using single nucleotide polymorphisms (SNPs) and interval mapping. QTL intervals will also be narrowed using bioinformatics including interval-specific haplotype analysis. For Aim 2 congenic strains of mice will be created by introgressing the QTL interval into inbred mouse strains and intermediate phenotypes characterized. In Aim 3, candidate genes will be identified using microarray analysis of skeletal muscle from congenic and inbred mice. Overall, these experiments will provide insight into the genetic basis for individual differences in the responses to exercise training as well as identify novel candidate genes that determine these individual differences. Because improving cardiorespiratory fitness through exercise training can significantly reduce the risk of cardiovascular disease, metabolic syndrome, and breast and colon cancer, understanding the genetic factors associated with the variability in the adaptation to exercise training may help to elucidate the mechanistic basis for chronic diseases associated with low levels of fitness.